This NIDA P50 Center would foster research interactions, promote exchange of ideas and technology and enhance the training environment in ways that will strongly advance drug abuse research at the University of Washington and will generate resources that will be made widely available. The Center would bring together a group of established investigators to focus on developing mouse models to resolve the molecular components underlying, drug abuse. Three projects within the Center address related questions: molecular mechanisms underlying opiate tolerance (Chavkin), molecular mechanisms underlying cannabinoid tolerance (Mackie), the specific role of protein kinase A in drug preference and sensitivity to amphetamine and cocaine (McKnight). These projects focus on the molecular basis of animal behavior controlled by drugs of abuse, and the design of the Center includes extensive collaborative interactions between these related projects. The Center would support core facilities required for efficient resource utilization and technique transfer within the projects: 1) a Mouse Genetics Core (Binion/McKnight) would facilitate the generation of new strains having tissue-specific, inducible mutations in key components of the animal?s response to opioid, cocaine and cannabinoid drugs; 2) the Behavioral Core (Bernstein & External Advisors) would standardize the analysis of drug effects and drug tolerance; and 3) the Anatomy Core (Westenbroek) would perform a generalized neuroanatomical characterization and maintain access to a confocal microscope facility. The third element of the Center is a Pilot Project component that initially would bring a distinguished scientist (Palmiter) into the drug abuse field, potentially bring other outstanding scientists (Catterall, Storm) into drug abuse research, and would help junior faculty (Stella, Brot) develop research programs in this area. All of the individuals listed would actively participate in regular progress meetings, training sessions, journal club and seminar programs, and Center retreats. The Center would expand the educational and training activities of an existing, NIDA Institutional training grant on the molecular pharmacology of abused drugs. Our prime motivation for establishing this Center is to enhance the intellectual, educational, and developmental interactions that would stimulate and expand drug abuse research. Synergy within the proposed Center would be derived from the transfer of ideas, techniques, expertise, perspective and mice between members of the group.